Regulation of vertebrate gastrulation by ErbB signaling

by Nie, Shuyi.

Abstract (Summary)

ErbB receptor tyrosine kinases have long been implicated in cancer formation and
progression by regulating cell division, migration, and survival. ErbBs are also essential
in multiple processes during invertebrate development; however, their activities during
vertebrate embryogenesis are not well understood. For functional characterization of
ErbB signaling during vertebrate development, frog model Xenopus laevis was used in
our studies. The expression pattern and the general activities of ErbB receptors during
early frog development were first analyzed and results shown that ErbBs regulate
gastrulation, somite organization and head patterning. As gastrulation is the first major
morphogenetic event in vertebrate development, I focused the following studies on ErbB
signaling in frog gastrulation. During Xenopus gastrulation, mesendodermal cells are
internalized and display different movements. Head mesoderm migrates along the
blastocoel roof, while trunk mesoderm undergoes convergent extension (C
&
E).
Inhibition of ErbB pathway blocks both C
&
E of trunk mesoderm and migration of head
mesoderm. Cell polarization and intercalation, cell-cell and cell-matrix interaction, as
well as formation of membrane protrusions are also impaired, demonstrating that
modulation of cell adhesive properties and cell morphology may underlie the functions of
ErbBs in gastrulation. These results reveal for the first time that vertebrate ErbB signaling
modulates gastrulation movements, thus providing a novel pathway, in addition to noncanonical
Wnt and FGF signals, that controls gastrulation. To further elucidate
mechanisms of ErbB signaling in Xenopus gastrulation, I next examined downstream
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signals employed by ErbBs during this process. From rescue experiments, PI3K and Erk
MAPK were shown to mediate ErbB signaling to regulate gastrulation morphogenesis.
Both PI3K and MAPK function sequentially in mesoderm specification and movements,
and ErbB signaling is important only for the late phase activation of these pathways.
While activation of either pathway rescues gastrulation defects induced by translational
inhibitory ErbB4 morpholino oligonucleotides, the two signals preferentially regulate
different aspects of cell behaviors. PI3K is more efficient in rescuing cell adhesion and
cell spreading while MAPK is more effective in stimulating the formation of filopodia.
The data reveal that PI3K and Erk MAPK, which previously considered as mesodermal
inducing signals, also act downstream of ErbB signaling to regulate gastrulation
morphogenesis.
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